ORGANIC LETTERS
Control of Phosphoryl Migratory Transesterifications Allows Regioselecive Access to Sugar Phosphates
2013 Vol. 15, No. 2 346–349
Mitul K. Patel and Benjamin G. Davis* Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
[email protected] Received November 28, 2012
ABSTRACT
Phosphate esters in polyhydroxylated systems are normally blighted by uncontrolled migration under a variety of reaction conditions. Cesium fluoride is demonstrated as a reagent to control migration of primary phosphates during transesterifications. This allows easy exchange of phosphoryl protecting groups enabling enhanced synthetic strategic flexibility and regioselective phosphate installation. Mechanistic analysis suggests that a fluoride-induced extended solvent sphere modulates steric bulk at phosphorus to favor the primary position.
Phosphorylated carbohydrates are prevalent in nature.1 Their central role in metabolism and signaling make them an important target for the synthetic chemist. However, carbohydrates (and inositols) have an inherent structural complexity that makes their selective phosphorylation difficult.2 Installation of phosphoryl groups usually requires multistep sequences that use protecting groups, which results in poor overall yields. Since the high polarity of unprotected phosphate groups can make conventional purification difficult,3 they are typically also protected to simplify handling. However, this strategy can cause further problems with orthogonality to other functional groups.2,4 In particular, the migration and cyclization of the phosphate group is a common problem requiring special attention.2 Neighboring hydroxyls, especially those in a (1) Bowler, M. W.; Cliff, M. J.; Waltho, J. P.; Blackburn, G. M. New J. Chem. 2010, 34, 784–794. (2) (a) Billington, D. C. Chem. Soc. Rev. 1989, 18, 83–122. (b) Billington, D. C. The Inositol Phosphates: Chemical Synthesis and Biological Significance; VCH: 1993. (c) Sureshan, K. M.; Shashidhar, M. S.; Praveen, T.; Das, T. Chem. Rev. 2003, 103, 4477–4504. (d) Chenault, H. K.; Mandes, R. F.; Hornberger, K. R. J. Org. Chem. 1997, 62, 331– 336. (e) Ahmadibeni, Y.; Parang, K. Org. Lett. 2005, 7, 1955–1958. (f) Ruhela, D.; Vishwakarma, R. A. J. Org. Chem. 2003, 68, 4446–4456. (3) Feurle, J.; Jomaa, H.; Wilhelm, M.; Gutsche, B.; Herderich, M. J. Chromatgr., A 1998, 803, 111–119. (4) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; John Wiley & Sons: New York, USA, 1999; pp 660 700. 10.1021/ol303271z r 2013 American Chemical Society Published on Web 01/03/2013
vicinal position, are well placed to attack the phosphorus center resulting in various side reactions. While protecting groups can lessen this problem, later deprotections may still expose neighboring hydroxyls to conditions favoring phosphate cyclization and migration, resulting in mixtures of polar compounds that can be extremely difficult to purify. For some compounds, catalysts5 can offer elegant, selective phosphorylations. However, for the majority of carbohydrates and inositols, phosphate migrations remain a major problem that can only be alleviated by careful planning of the synthesis. We sought conditions to access cyclic phosphate intermediates, the ‘opening’ of which could parallel the wellexploited 4,6-O-benzylidene ring openings where the choice of reagent allows excellent regioselective control.6 Under acid catalysis, electronic control dictates protonation leading (5) (a) Nakajima, H.; Kondo, H.; Tsurutani, R.; Dombou, M.; Tomioka, I.; Tomita, K. Enzymes in Carbohydrate Synthesis; American Chemical Society: Washington, DC, 1991; pp 111 120. (b) Chenault, H. K.; Mandes, R. F.; Hornberger, K. R. J. Org. Chem. 1997, 62, 331–336. (c) Sculimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc. 2001, 123, 10125–10126. (6) (a) Preparative Carbohydrate Chemistry; Hanessian, S., Ed.; Marcel Dekker: New York, 1997; pp 53 68. (b) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; 3rd ed.; John Wiley & Sons: New York, 1999; pp 217 224. (c) Shie, C.-R.; Tzeng, Z.-H.; Kulkarni, S. S.; Uang, B.-J.; Hsu, C.-Y.; Hung, S.-C. Angew. Chem., Int. Ed. 2005, 44, 1665–1668.
to the 6-ether, but bulky Lewis acids furnish the 4-ether, via sterically more favorable 6-O activation. For phosphates, the steric requirements of the implicated pentacoordinate intermediates might allow similarly good electronic or solvent-mediated control.
Table 1. Attempted Direct
OPh f
OH Deprotectiona
Scheme 1. Strategies for Regioselective Sugar Phosphorylation entry
Rb
conditions
time
3/%
4/%
5/%
1 2 3
a a a
A A B
10 min 14 h 12 h
88 93 49
0 0 31
9 0 0
a
Conditions: (A) NH4OH, H2O, tBuOH; (B) 10 equiv of CsF, H2O, 80 °C. b For the structures of sugar structures used in this paper please refer to Scheme 1.
Scheme 2. ArO f OH Exchange during Hydrolysis Leads to Irreversible Entry into a Charged Cyclic Phosphate Manifold
This suggested a phosphorylation strategy with a bis-protected phosphoryl unit followed by cyclization and controlled opening (Scheme 1, path a). If combined with transesterification this could allow ready manipulation of phosphoryl substituents. Such control of migration would also allow potential for regioconvergence from an initially poorly regioselective phosphorylation. Trehalose, the R,R-1,1-nonreducing dimer of D-glucose, has a complex polyhydroxylated structure that makes it a particularly excellent test substrate. Its 6-O-phosphate has been previously synthesized using chemical (POCl3,7 sodium phosphate8) or enzymatic methods.9 We have previously shown that diphenyl chlorophosphate can be used to regioselectively install phenyl-protected phosphate groups onto trehalose.10 Direct hydrolytic PhO f OH exchange in 2a was tested first (Table 1), initially with basic hydrolysis.11 On exposure of 2a to ammonium hydroxide, cyclic phosphate 3a was produced in 88% yield within 10 min (entry 1); with short reaction times, 9% of the partially deprotected, but (7) Rønnow, E. C. L.; Meldal, M.; Bock, K. Carbohydr. Res. 1994, 260, 323–328. (8) Tarelli, E.; Wheeler, S. F. Carbohydr. Res. 1994, 261, 25–36. (9) (a) Doi, J.; Yokoigawa, K.; Isobe, Y.; Kawai, H. Biosci., Biotechnol., Biochem. 1998, 62, 735–739. (b) Errey, J. C.; Lee, S. S.; Gibson, R. P.; Fleites, C. M.; Barry, C. S.; Jung, P. M. J.; Sullivan, A. C. O.; Davis, B. G.; Davies, G. J. Angew. Chem., Int. Ed. 2010, 49, 1234–1237. (10) Patel, M. K.; Davis, B. G. Org. Biomol. Chem. 2010, 8, 4232– 4235. (11) (a) Plourde, R.; d’Alarco, M. Tetrahedron Lett. 1990, 31, 2693– 2696. (b) Nanteuil, G. D.; Benoist, A.; Remond, G.; Descombes, J.; Barou, V.; Verbeuren, T. J. Tetrahedron Lett. 1995, 36, 1435–1438. Org. Lett., Vol. 15, No. 2, 2013
migrated, 4-O-phosphate 5a was also isolated. None of the directly deprotected 6-O-phosphate was observed. Over longer reaction times, 5 was not isolated and 3a was the sole product (entry 2). Importantly, use of CsF12 (entry 3) hinted at the potential for migration that might be exploited later. While phosphate cyclization remained the predominant pathway (3 in 49% yield), these conditions also gave 4a, which crucially had retained the phosphoryl group at the O-6-position. These results may be rationalized via an entropically favored intramolecular cyclization giving cyclic ester 6 (Scheme 2).13 Hydroxyl ion attack gives a pentacoordinate intermediate (PI2) leading to three possible products (12) Ogilvie, K. K.; Beaucage, S. L. Nucleic Acids Res. 1979, 7, 805– 823. (13) (a) Fordham, W. D.; Wang, J. H. J. Am. Chem. Soc. 1967, 89, 4197–4203. (b) Buchwald, S. L.; Pliura, D. H.; Knowles, J. R. J. Am. Chem. Soc. 1984, 108, 4916–4922. (14) (a) Westheimer, F. H. Science 1987, 235, 1173–1178. (b) Schroeder, G. K.; Lad, C.; Wyman, P.; Williams, N. H.; Wolfenden, R. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 4052–4055. 347
Table 2. Conditions for Controlled Transesterificationa
R
conditions
yieldb/ %
rrc 8:9/%
1
a NEt3 (1 equiv), MeOH, 3 h
54
37
63
2 3 4 5
a a a a
CsF (2.5 equiv), MeOH CsF (10 equiv), MeOH KF (10 equiv), MeOH TBAF (10 equiv), MeOH
91 94 93 51
58 65 61 85
42 35 39 15
a CsF (10 equiv), DMF/MeOH (1:1) 7 a CsF (10 equiv), tBuOH/MeOH (1:1) 8d a CsF (10 equiv), H2O/tBuOHd (1:3) 9 a CsF, NH3, MeOH, pH 13 10 a CsF, HCl, MeOH, pH 2 11 a CsF (10 equiv), MeOH, 50 °C 12 a CsCl (10 equiv), MeOH
59
other products 7a (22%)
13 a MgCl2 (10 equiv), MeOH
0
14 a Na2CO3 (2.5 equiv), DCM/MeOH (4:1), 80 h 15f a Ionic liquid/MeOH (1:1), 18 h, NEt3 (4 equiv)f
34
3a (24%) 55 45 3a (22%) 59 41 3a (11%) 3a 100d 0d (49%) 64 36 68 34 63 37 0 0 3a (82%) 0 0 3a (85%) 32 68 e
57
100 0
6
62 31 92 93 90 0
a Reactions were performed under reflux for 16 h unless otherwise noted. b Combined yield. c Regioselectiviy ratio normalized as %, determined by 1H NMR of crude mixture and HPLC. d From Table 1 giving 4 and 5. e Minor O-2,3 migration products. f Conducted in dimethylimidazolium dimethylphosphate and per-O-acetylated to aid purification.
(3, 4, or 5). Of these, the diester 3 exists in deprotonated form, and the repulsive effects of this charge are the source of extreme hydrolytic stability.1,14 Thus, nucleophilic attack on 3 is disfavored and its formation is irreversible, while 4 and 5 are still inclined to cyclization and so are formed reversibly; over time the cyclic phosphate 3 is the major product. We reasoned that OPh f OR transesterification would produce a cyclic phosphate intermediate that would not be charged and could therefore be formed reversibly. Hence, we tested reactions using MeOH as solvent (Table 2). Initial investigations under strongly basic conditions resulted in BAl2/SN2-type solvolysis of exchanged intermediates leading to monodeprotection and entry into the unwanted charged cyclic phosphate (3) manifold. Under milder conditions methyl loss did not occur; we were pleased to see that uncharged cyclic phosphate 7a was quickly formed and, over time, reacted further to give 8a and 9a. Thus, triethylamine (entry 1) allowed 348
transesterification without concomitant deprotection albeit with substantial migration from O-6 to O-4 (63% r.r. O-4 9a). In the presence of CsF (entries 2, 3), O-4 migration was reduced in a manner dependent on the amount of CsF used, up to 10 equiv, which gave 65% r.r. of O-6 8a. Importantly, these results demonstrated entry into a manifold primed for migration and suggested that regioselectivity could be modulated. A striking feature of these reactions was the reduced propensity for O-4 migration in the presence of CsF. The reasons for these altered migratory properties were investigated (Table 2). First, other fluoride salts with increasing organic solubility (entries 4f3f5) reduced migration to O4. Similarly, increasing solvent proticity15 (entries 6f7f3f8) also decreased migration. Third, the reaction was found to be essentially insensitive to pH (entries 9 and 10) and temperature (entry 11). Finally, with the different counteranion Cl (entries 12, 13) 3a was formed exclusively, presumably through Krapcho-type demethylation.16 Notably, fluorophosphates (potentially isolable compounds17) were not detected in any reactions, ruling out direct fluoride participation (see Supporting Information (SI) for control reactions). It is worth noting that, over longer reaction times (entry 14), further migration to O-2 and O-3 was observed. These studies revealed that we were able to tune regioselective ratios from 68% in favor of one regioisomer, 9, to 100% of the other, 8, using appropriate conditions. To test the scope of this strategy, we applied CsF-mediated transesterification to other biologically relevant carbohydrates (Table 3). The required starting diphenylphosphates were synthesized in an analogous manner to that used for 2a.10 Pleasingly, subsequent transesterifications for 2b d all proved successful, indeed more so than for 2a. Thus, glucoside 2b gave the O-6-phosphate 8b as the major product in 72% yield. Similarly, mannoside 2c furnished the desired O-6-phosphate 8c in an excellent 84% yield. For galactoside 2d, the initial cyclization was slower (presumably due to the more hindered axial position of OH-4) and the reaction required 40 h for completion. Migratory ring opening exclusively yielded the O-6-phosphate 8d in 96% yield. Riboside 2e was also successful (8e, 96%); this proceeded via a mixed rather than cyclic ester intermediate (see SI for details). Deprotections (Table 3) of these dimethylphosphates 8a e were achieved with TMSI18 in excellent yields of greater than 85% for all. The protocol we describe allows control of regiochemistry during phosphoryl migrations, which occur via a cyclic intermediate13 with the outcome dictated by a (15) (a) Kamlet, M. J.; Taft, R. W. J. Am. Chem. Soc. 1976, 98, 377– 383. (b) Taft, R. W.; Kamlet, M. J. J. Am. Chem. Soc. 1976, 98, 2886– 2894. (16) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J. Tetrahedron Lett. 1967, 8, 215–217. (17) (a) Gupta, A. K.; Acharya, J. D.; Pardasani, D.; Dubey, D. K. Tetrahedron Lett. 2008, 49, 2232–2235. (b) Furegati, S.; Ganci, W.; Gorla, F.; Ringeisen, U.; R€ uedi, P. Helv. Chim. Acta 2004, 87, 2629– 2661 and references therein for preparation, isolation, and even reaction in alcoholic solvents of fluorophosphates. (18) (a) Blackburn, G. M.; Ingleson, D. J. Chem. Soc., Chem. Commun. 1978, 870–871. (b) Olah, G. A.; Narang, S. C. Tetrahedron 1982, 38, 2225–2277. Org. Lett., Vol. 15, No. 2, 2013
Table 3. Transformations to 8, 9, and 10a
Scheme 3
entry
starting 2
time/ h
yield 9/%b
yield 8/%b
yield 10/%c
1 2 3 4 5
a b c d e
16 16 16 40 16
33 18 5 0 0
61 72 84 96 96
87 88 86 92 87d
a Conditions: (i) CsF (10 equiv), MeOH, reflux; (ii) TMSI, dioxane, 15 min, rt. b Isolated from step (i). c Isolated from step (ii). d C-1 epimer seen.
pentacoordinate P center (Scheme 3).19 A kinetic preference for migration to OH-4 (cf. Table 2, entry 14), observed previously,20,21 can be explained by apicophilicity of the most electronegative, primary OH-6 in 11 (see SI for discussion);20,22,23 extrusion of the longer P O(6) bond would be more facile giving 9. However, sterics may override electronics.22 F ions interact strongly with hydroxyls24 and create H-bonding networks within solvent25 (described as “structure markers” that increase solvent ordering26) particularly in methanolic solutions of CsF.27,28 This suggests that F-mediated H-bonding may create a large solvation sphere around the charged phosphoryl group (12, Scheme 3). The increased bulk at OH-4 would then overcome the apicophilicity of OH-6. This effect would be more (19) (a) Westheimer, F. H. Acc. Chem. Res. 1968, 1, 70–78. (b) Dennis, E. A.; Westheimer, F. H. J. Am. Chem. Soc. 1966, 88, 3432–3433. (c) Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D. Angew. Chem., Int. Ed. 1973, i, 91–119. (20) Hall, C. R.; Inch, T. D. Tetrahedron 1980, 36, 2059–2095. (21) (a) Cooper, D. B.; Harrison, J. M.; Inch, T. D.; Lewis, G. J. J. Chem. Soc., Perkin Trans. 1 1974, 1058–1068. (b) Szabo, P.; Szabo, L. J. Chem. Soc. 1960, 3758–3762. (c) Inch, T. D.; Lewis, G. J. J. Chem. Soc., Chem. Commun. 1973, 310–311. (22) Trippett, S. Phosphorus Sulfur 1976, 1, 89–98. (23) (a) Mikhailov, S. N.; Oivanen, M.; Oksman, P.; Lonnberg, H. J. Org. Chem. 1992, 57, 4122–4126. (b) Oivanen, M.; Schnell, R.; Pfeiderer, W.; L€ onnberg, H. J. Org. Chem. 1991, 56, 3623–3628. (c) J€ arvinen, P.; Oivanen, M.; L€ onnberg, H. J. Org. Chem. 1991, 56, 5396–5404. (24) Gonz alez, R.; Ortiz, P.; Reguera, E.; Bertran, J. F. J. Fluorine Chem. 2001, 110, 5–10. (25) (a) Hefter, G. T. Pure Appl. Chem. 1991, 63, 1749–1758. (b) Hefter, G. T.; McLay, P. J. J. Sol. Chem. 1988, 17, 535–546. (26) Frank, H. S.; Wen, W. Y. Disc. Faraday Soc. 1957, 24, 133–140. (27) Marcus, Y.; Hefter, G. Chem. Rev. 2006, 106, 4585–4621. (28) Hefter, G. T.; Salomon, M. J. Sol. Chem. 1996, 25, 541–553.
Org. Lett., Vol. 15, No. 2, 2013
pronounced in D-galactosides and is consistent with the trend seen for 2df8d (Table 3, entry 4). A similar unusual role for CsF in reaction selectivity has also been noted previously in Michael additions.29 Based on this analysis, a reaction was performed in an ionic liquid (Table 2, entry 15) that possesses a highly ordered long-range structure30 and therefore similarly large solvation spheres. We chose a dimethylphosphate derived ionic liquid to prevent interference from the anion.31 Under reflux in a 1:1 ratio with methanol and 4 equiv of NEt3 as base, the reaction gave a highly regioselective ratio of >98% for 8a, consistent with the solvent sphere hypothesis. In this paper, we have demonstrated methodology that can offer regiocontrol of phosphate migrations. This now enables phosphate transesterification and substituent exchange with all of the associated synthetic strategic advantages. Crucially, exchange of protecting groups allows the introduction of phosphates through a bulky phosphorylating agent prior to alteration to something with orthogonality that allows removal under conditions compatible with other functionality. We believe that this approach will prove useful for installation of the key sugar modification of phosphorylation and may prove applicable to other vital modifications such as sulfation. Supporting Information Available. Experimental details. This material is available free of charge via the Internet at http://pubs.acs.org. Acknowledgment. We thank the International AIDS Vaccine Initiative for funding. B.G.D. is a Royal Society Wolfson Research Merit Award recipient. (29) Ishikawa, T.; Oku, Y.; Kotake, K.; Ishii, H. J. Org. Chem. 1996, 61, 6484–6485. (30) Hardacre, C.; Holbrey, J.; Nieuwenhuyzen, M.; Youngs, T. G. A. Acc. Chem. Res. 2007, 40, 1146–1155. (31) If substitution were to occur, 8a would be formed (rather than side products that would result with other ionic liquids). The authors declare no competing financial interest.
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